Interferon-g (IFN-g) a cytokine that is dysregulated in children with AIDS, has bidirectional effects on HIV infection of macrophages. The C-C (B) chemokine receptor CCR5 is a major fusion co-receptor for HIV infection of macrophages. We studied the effect of IFN-g on CCR5 expression in mononuclear phagocytes isolated from cord (n=7) and adult blood (n=7) of healthy donors. Freshly isolated monocyte and monocyte- derived macrophages (MDM) treated with IFN-g showed significantly increased CCR5 expression compared to control cells, as demonstrated by immunofluorescence staining and flow cytometry. Monocytes and MDM from cord and adult blood showed similar levels of CCR5 expression, in the resting state and in response to IFN-g. RT-PCR analysis demonstrated increased CCR mRNA in IFN-g-tretated monocytes. Monocytes treated with IFN-A and IFN-B did not show significant changes in CCR5 expression in mononuclear phagaocytes. IFN-g also upregulates secretion of C-C chemokines (MIP-1A, MIP-1B and RANTES) by mononuclear phagocytes. We conclude that IFN-g up-regulates CCR5 expression in mononuclear phagaocytes. We speculate that modulation of HIV infection of macrophages by IFN-g occurs in part by regulation of CCR5 expression. The balance between up-regulation of CCR5 expression and C-C chemokine secretion may play a critical role in determining the enhancing versus suppressing effects of IFN-g on HIV infection of macrophages.